Getinge Ab Class B · OMXSTO:GETI_B
Getinge Ab Class B — Technical Presentation (2015)
27 slides from Getinge Ab Class B's technical presentation, 2015
Slide 1: Module 2: The Clinical Enigma: Randomized Trials vs Clinical Practice
MODULE 2 THE CLINICAL ENIGMA: RANDOMIZED TRIALS vs CLINICAL PRACTICE Nico H. J. Pijls, MD, PhD Catharina Hospital Eindhoven The Netherlands
Slide 2: Disclosure and Disclaimer – Indications
Disclosure All presenters have a speaker agreement with Maquet Disclaimer – Indications The content of this presentation represents a medical practioner’s authorized practice of medicine in the exercise of appropriate medical judgment for the best interest of the patient. Refer to Maquet’s Instructi
Slide 3: Key points in this presentation
Key points in this presentation: • Why did current prospective trials with IABP not meet their endpoints • The emerging science of selection of patients who may benefit from IABP
Slide 4: IABP: Clinical Enigma
IABP: CLINICAL ENIGMA: • In some patients dramatic improvement of clinical condition by IABP • In others no effects at all • Many retrospective studies show benefits • In prospective randomized studies no differences WHY those differences? How to select patients and clinical conditions which benefit
Slide 5: SHOCK II Trial
SHOCK II Trial • 600 patients with acute MI, complicated by cardiogenic shock and planned primary PCI • Randomized to PCI + IABP or PCI only • Primary endpoint: 30-day mortality • High cross-over rate in PCI only group: - 10% to IABP, and ~5 % to LVAD/Impella/etc • Crossover rate 4 % in IABP group,
Slide 6: SHOCK II Trial
SHOCK II Trial High cross-over rate of 15 % in PCI only group: 10% to IABP, and ~5 % to LVAD/Impella/etc The worst patients from the control group received additional treatment which - at least at the judgement of the treating physician - was considered useful (positive bias in favor of control grou
Slide 7: SHOCK II Trial
SHOCK – II Trial Crossover rate 4 % in IABP group, due to immediate death before IABP could be started The patients from the “treatment”group who would have the highest profit of IABP, contributed in negative sense for the endpoint (negative bias for the “treatment group”
Slide 8: SHOCK II Trial: selective cross-over
SHOCK II Trial So-called “selective cross-over” (NTVG 2013; 157: 2151-2155) serious bias If use of additional support device would have been part of primary endpoint positive study Thiele et al, NEJM 2012
Slide 9: CRISP AMI Trial
CRISP AMI TRIAL • 339 patient with STEMI ≤ 6 Hours admitted for primary PCI • 2 palpable femoral arteries • ECG with Anterior STEMI (2 mm in 2 Leads or ≥ 4 mm total) • Randomized to IABP / no IABP prior to PCI • Endpoints: - Infarct size after 5 days by MRI - Manifest heart failure at 6 months
Slide 10: Outcomes of CRISP AMI
Outcomes of CRISP AMI • No difference in infarct size (or any other MRI parameter) • At 6 months – 3 patients IABP plus PCI died, vs. 9 patients PCI alone (strong trend) • Significant difference in non- specified composite endpoint of death, shock or heart failure – 8 vs. 21 events at 6 months P=0.0
Slide 11: Limitations of CRISP AMI
Limitations of CRISP AMI • Inclusion criteria not “robust” enough - In many patients (56%) limited amount of myocardium at risk dilution of benefit (in fact, the study was severely underpowered) • If good “reflow” after PCI (as is the case in many patients), good outcome anyway further dilution
Slide 12: CRISP AMI: 30-day mortality
CRISP AMI: 30-day mortality no noIABP IABP no IABP no IABP IABP IABP IABP IABP All patients (N=329) “Large” infarction (N=146) Persistent ischemia (N=36) IABP significantly reduced mortality in large STEMI with persistent ischemia Van Nunen et al, EuroIntervention 2015 (in press)
Slide 13: Is an Intention-to-Treat analysis suitable?
Is an Intention-to-Treat analysis suitable to analyze this kind of studies? No Prerequisites for an Intention-to-Treat analysis: • Double-blind study • Large sample size • Events relatively rare compared to sample size • Low and non-selective cross-over rate Especially if cross-over is driven by fai
Slide 14: Is an "as treated" analysis suitable?
Is an “as treated” analysis then suitable to analyze these kind of studies? (as suggested by the authors of SHOCK-2) • In case of high asymmetrical cross-over rate, the baseline characteristics of the groups change considerably (the worst patients from the “control group” are moved to the “device” g
Slide 15: Bias and confounding in IABP RCTs
• In the prospective RCT’s to the benefits of IABP, serious negative bias and confounding was present, masking by definition potentially positive effects of IABP • This is a fundamental problem in open studies in “back-to-the wall” patients with high mortality, like many other studies in Intensive C
Slide 16: When does a balloon pump make sense?
When does a balloon pump make sense ? • Increase of (diastolic) perfusion pressure does NOT increase coronary blood flow and oxygen supply under normal physiologic circumstances (autoregulation counteracts IABP effects) In normal circumstances, cannot expect noticeable effect of IABP on coronary blo
Slide 17: Coronary autoregulation is exhausted in case of
Coronary autoregulation is exhausted in case of: • Low (diastolic) blood pressure (< 60 mmHg) • Very tight (critical) stenosis • Ongoing myocardial ischemia: Acute phase of MI with no/insufficient reflow Sometimes the patient after cardiac surgery Under these circumstances, coronary blood flow is di
Slide 18: Large STEMI: When to Use IABP?
Large STEMI: When to Use IABP ? Hypothesis: IABP may be expected to be useful in patients with viable myocardium suffering from persistent ischemia despite an unobstructed coronary artery How to validate this??
Slide 19: Isolated beating pig heart
Isolated beating pig heart http://repository.tue.nl/posters/762328.pdf
Slide 20: Beating heart model with independent control
Beating heart model with independent control of: • Afterload (blood pressure) • Preload (LA pressure) • Contractility (dP/dt) • Arterial oxygen saturation • Heart rate Measurement of these parameters and in addition: • Cardiac output • Coronary blood flow • Myocardial oxygen consumption http://repos
Slide 21: Ex-vivo animal model
In this ex-vivo animal model : • Autoregulation was switched off • Pump failure / cardiogenic shock could be imitated • Large myocardial infarction with persistent ischemia could be induced Effect of IABP was tested in all these different clinical scenario’s of persistent ischemia whether or not sup
Slide 22: Effects of IABP on coronary blood flow and cardiac output
Percentage Change w.r.t. Baseline [%] 0 10 20 30 40 50 60 CO M = H AP 5 . e 5 = ± alt 84 0. h ± 4L y 4 /m m i P CO r m n e Hg M = - AP 4. S Ischemic 3 h = ± o 72 0 . c ± 3L k 3 /m (A) Non-Ischemic m i m n Hg M AP C S Coronary flow = O =h 63 3 o ± .3 ck 3 ± m 0. m 3 Hg and without persistent ischemia
Slide 23: Myocardial oxygen consumption
72 0 . o c ± 3L k 3 /m (B) m in m Hg M AP C S = O = ho ac Output 63 3 c ± .3 k 3 ± m 0. m 3 Hg No ischemia: Percentage Change w.r.t. Baseline [%] -10 0 10 20 30 40 CO M = H AP 5 e . = 5 ± al 84 0 th ± .4 L y 4 /m m P CO r m in Hg M = - e AP 4 S . = 3 ± ho 72 0 c ± .3 L k 3 /m (C) m i m n Hg M AP C S
Slide 24: Conclusions 1
Conclusions: 1. Several large prospective RCT’s like SHOCK II and CRISP-AMI are hampered by: • Inappropriate patient selection • Inappropriate statistical analysis As a consequence, such trials should be considered as non-conclusive
Slide 25: Conclusions 2
Conclusions: 2. IABP may be particularly useful in patients with viable myocardium suffering from persistent ischemia despite an unobstructed coronary artery • Acute STEMI, successful epicardial stenting, no- reflow • Cardiac surgery, good bypasses, stunning
Slide 26: SEMPER FI study
SEMPER FI study Survival in Extensive Myocardial Infarction with PERsistent Ischemia Following IABP • Recently started, prospective RCT in patients with large myocardial infarction (summed ST-elevation ≥ 15 mm) • Primary PCI, ECG immediately following PCI (< 10 min) • If ST-resolution is < 50% rando
Slide 27: Summary
Summary • Discussed recent clinical trials & why they apparently have not shown a clear benefit • A model has been developed to prove the role of IABP and has shown that persistent ischemia seems to be a pre-requisite for IABP • This is being investigated in the SEMPER FI trial ML 0549-07 Rev MCV 00